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Integrated Exploitation of the Structural Diversity Space of Chemotherapy Drugs to Selectively Inhibit HER 2 T798M Mutant in Lung Cancer
Author(s) -
Wang YaWei,
Zhang HaiYan,
Li JiSheng,
Wang XiuWen
Publication year - 2017
Publication title -
chemistry and biodiversity
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.427
H-Index - 70
eISSN - 1612-1880
pISSN - 1612-1872
DOI - 10.1002/cbdv.201600301
Subject(s) - mutant , chemistry , lung cancer , chemotherapy , diversity (politics) , cancer , cancer research , mutation , biochemistry , biology , genetics , gene , medicine , sociology , anthropology
An acquired T798M gatekeeper mutation in human epidermal growth factor receptor 2 ( HER 2) kinase can cause drug resistance to anti‐ HER 2 chemotherapy drugs in lung cancer. Previously, the reversible pan‐kinase inhibitor staurosporine has been found to selectively inhibit the HER 2 T798M mutant over wild‐type kinase, suggesting that the staurosporine scaffold is potentially to develop mutant‐selective inhibitors. Here, we systematically evaluated the chemical space of staurosporine scaffold‐based compounds in response to HER 2 T798M mutation at structural, energetic and molecular levels by using an integrated analysis strategy. With this strategy, we were able to identify several novel wild‐type sparing inhibitors with high or moderate selectivity, which are comparable to or even better than that of the parent compound staurosporine. Molecular modeling and structural analysis revealed that noncovalent contacts can form between the side chain of mutated residue Met798 and selective inhibitor ligands, which may improve the favorable interaction energy between the kinase and inhibitor and reduce the unfavorable desolvation penalty upon the kinase–inhibitor binding.